Automatic lung parameter estimator

ABSTRACT

A device for determining one or more respiratory parameters relating to an individual is disclosed, as well as a method for determining one or more respiratory parameters by means of the device, wherein the individual is suffering from hypoxemia or is at risk of hypoxemia. However, the method and the device may also be applied to healthy individual e.g. for testing of medicaments. The device is controlled by a computer equipped with suitable software and includes functionality for on-line continuous data collection, automatic assessment of the timing of measurements, automatic assessment of the next target (oxygen saturation of arterial blood (SpO2)), automatic assessment of the appropriate fraction of oxygen in inspired gas (FIO2) settings to achieve the target SpO2, automatic control of the FIO2, on-line parameter estimation, and automatic assessment of the number of measurememts requied.

This application is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/DK00/00040 which has an Internationalfiling date of Feb. 1, 2000, which designated the United States ofAmerica and was published in English.

The present invention relates to a device for determining one or morerespiratory parameters relating to an individual. The device may includefunctionality for on-line continuous data collection, automaticassessment of the timing of measurements, automatic assessment of thenext target (oxygen saturation of arterial blood (SpO₂)), automaticassessment of the appropriate fraction of oxygen in inspired gas (FIO₂)settings to achieve the target SpO₂, automatic control of the FIO₂,on-line parameter estimation, and automatic assessment of the number ofmeasurements required. This functionality is achieved through a noveldevice including ventilatory equipment, blood gas analysis equipment andcomputer hardware and software.

Furthermore, the present invention relates to a method for determiningone or more respiratory parameters by means of the above-mentioneddevice, wherein the individual is suffering from hypoxemia or is at riskof hypoxemia. The individual may also be a healthy individual.

The use of the device for examination and monitoring respiratoryparameters relating to humans are of particular interest, but the devicemay also be applied to farm animals such as pigs, or to domestic animalssuch as dogs.

BACKGROUND

Oxygen enters the body with inspiration and diffuses from the lungs intothe blood. Subsequently the blood circulation transports oxygen to thetissues. Disorders of oxygen transport from the inspired air into theblood can result in a low oxygen saturation of the blood. Thesedisorders in oxygen uptake include abnormal ventilation of the lung,seen in for example chronic obstructive pulmonary disease; abnormaloxygen diffusion in the lung, seen in for example pulmonary fibrosis;and abnormal perfusion (i.e. blood flow) through the lung. Estimation ofparameters describing these oxygenation problems is important fordiagnosis, monitoring and assessing appropriate therapeuticintervention. This is true in a wide variety of patients, from those whoare automatically ventilated and who often require continuous supplementof oxygen, to out-patients who only suffer from dyspnoe during exercise.

In clinical practice the clinician usually relies upon simplemeasurements or variable estimates to assess the patients oxygenationproblems. These include qualitative estimates obtained from stethoscopyor chest X-ray. They also include more quantitative estimates such asarterial oxygen saturation, the alveolar-arterial oxygen pressuregradient, or estimates of the “effective shunt”, a parameter whichdescribes all oxygenation problems in terms of a fraction of blood whichdoes not flow through the lungs (Siggaard-Andersen andSiggaard-Andersen, 1985).

Whilst the “effective shunt” is a parameter which has been used widelyin the clinical literature it cannot adequately describe the ‘clinical’picture seen in patients when the inspired oxygen fraction is varied.This observation is illustrated in FIG. 1 where the “effective shunt”has been estimated for a single patient at four different inspiredoxygen fractions, and varies from 15–25%.

In contrast to the poor clinical description of oxygenation problems,detailed experimental techniques such as the Multiple Inert GasElimination Technique (MIGET) (Wagner et al., 1974) have been developedwhich describe the parameters of models with as many as fifty lungcompartments. The parameters of these models give an accuratephysiological picture of the patient. Whilst the MIGET has foundwidespread application as an experimental tool its use as a routineclinical tool has been somewhat limited (Wagner et al., 1987). This islargely due to the cost and complexity of the technique.

As stated previously, “effective shunt” is insufficient to describeoxygenation problems. Further parameters describing the patient'soxygenation problem can be obtained from data where inspired oxygen isvaried, i.e. data similar to that presented in FIG. 1. This was firstrecognised by Riley et al. (1951a, 1951b) and later by King et al.(1974). These authors used mathematical models to divide the oxygenationproblem into that due to an alveolar-lung capillary drop in the partialpressure of oxygen, and that due to a shunt problem. To estimate twoparameters describing the oxygenation problem requires takingmeasurements of blood samples and of ventilatory variables at eachinspired oxygen fraction. Estimating lung parameters using the data fromfour inspired oxygen fractions required four blood samples, a procedurewhich is still rather time consuming and in some environmentsimpractical.

More recently, development of non-invasive methods for measuring theoxygen saturation of the blood have lead to renewed interest inestimation of parameters describing oxygen transport obtained by varyingFIO₂. Andreassen et al. (1996, 1999), Sapsford et al. (1995), de Gray etal. (1997) and Roe et al. (1997), have presented the use of twoparameter mathematical models of oxygen transport, the oxygenationproblem being described as shunt combined with either a diffusionabnormality (Andreassen et al. (1996, 1999)) or due to aventilation/perfusion (

) mismatch (Sapsford et al. (1995), de Gray et al (1997), Roe et al.,(1997)). These model representations have been shown to provideidentical fits to routine blood gas and ventilatory data obtained byvarying FIO₂ (Rees et al. 1997).

The clinical relevance of the two parameter models is illustrated inFIG. 2, where increases in the pulmonary shunt parameter results in avertical depression of the FIO₂/SaO₂ curve, (V-shift) and abnormalitiesin the second parameter (ventilation/perfusion (

) mismatch or oxygen diffusion resistance (Rdiff)) results in a lateraldisplacement of the FIO₂/SaO₂ curve. Clearly, the lateral displacementof the FIO₂/SaO₂ curve (H-shift) is clinically a more significantproblem as it describes a situation where large changes in oxygensaturation can occur for only small changes in FIO₂. In this situationthe patient is at increased risk of an oxygenation problem.

The two parameter model of Sapsford et al. (1995), has been shown to fitdata from normal subjects; patients before and after thoracotomy(Sapsford et al. 1995, de Gray et al., 1997); and patients during(Sapsford et al. 1995, Roe et al., 1997), and after (Roe et al., 1997)abdominal surgery. Similarly, the two-parameter model described byAndreassen et. al. has been shown to fit data from normal subject andpostoperative cardiac patients (Andreassen, 1999) and a wide range of asyet un-published results. Examples of these results are shown in FIG. 3.

In contrary to detailed experimental approaches (e.g. the MIGET), thesetwo parameter models can be used routinely in clinical practice. Inparticular, these techniques may find application in the monitoring andchoice of therapeutic treatment for patients with left-sided heartfailure, or to assess patients risk of post-operative hypoxaemia.

Until now, estimation of oxygenation parameters has involved manualtitration of the FIO₂/SaO₂ curve and off-line estimation of theparameter values. This is time consuming with experimental times ofapproximately 45 minutes, not including the time required for off lineparameter estimation. This limits the use of the method as a clinicaltool.

DESCRIPTION OF THE INVENTION

It is an object of the present invention to provide a device forestimation of one or more respiratory parameters including oxygenationparameters and lung parameters relating to an individual in which thenecessary quantities for enabling an estimation of respiratoryparameters are collected automatically by a computer of the device so asto provide an automated estimation of said parameters.

It is a further object to provide a device wherein the necessarymeasurements at varying oxygen levels are obtained in an at leastsemi-automated manner whereby the experimental time for said estimationmay be reduced. By reducing the procedural time these techniques havepotential for routine clinical use.

It is a still further object to provide a device which is adapted forassessing a possible new target of the level of oxygen in the bloodcirculation based on the previously obtained measurement(s).

It is a yet still further object to provide a device, which is adaptedfor assessing an appropriate change in the current level of oxygen inthe inspired gas to obtain a given target of the level of oxygen in theblood circulation.

The use of the device on humans is of particular interest, but thedevice may also be applied to farm animals such as pigs, or to domesticanimals such as dogs.

The device might be of value in all kind of patients in which hypoxemiaoccurs or may occur. These conditions may e.g. be selected from thegroup comprising left sided heart failure, adult respiratory distresssyndrome, pneumonia, postoperative hypoxemia, pulmonary fibrosis, toxicpulmonary lymphoedema, pulmonary embolisms, chronic obstructivepulmonary disease and cardiac shunting.

Thus, the present invention relates in a first aspect of the presentinvention to a device for determining one or more respiratory parametersrelating to an individual, comprising

-   -   a gas flow device having means for conducting a flow of        inspiratory gas from an inlet opening to the respiratory system        of the individual and a flow of expiratory gas from the        respiratory system of the individual to an outlet opening,    -   a gas-mixing unit for supplying a substantially homogeneous gas        to the inlet opening of the gas flow device,    -   first supply means for supplying a first gas to an inlet of the        gas mixing unit and having first control means for controlling        the flow of the first gas,    -   second supply means for supplying a second gas having an oxygen        fraction different to the gas supplied from the first supply        means to an inlet of the gas mixing unit and having second        control means for controlling the flow of the second gas,    -   a computer for determining said one or more respiratory        parameters,    -   first detection means for detecting the level of oxygen (SaO₂,        SpO₂, PaO₂, PpO₂) in the blood circulation of the individual and        producing an output to the computer accordingly, and    -   second detection means for detecting the level of oxygen (FIO₂,        FE′O₂, FĒO₂, PIO₂, PE′O₂, PĒO₂) in the gas flow passing into or        out of the respiratory system of the individual and producing an        output to the computer accordingly, the computer being adapted        for retrieving and storing at least two measurements being the        concurrent output produced by the first detection means and the        second detection means within a data structure, in which the two        stored outputs are mutually related, in data storage means        associated with the computer, the at least two measurements        being conducted at respective levels of oxygen in the gas flow        passing into the respiratory system, the computer further being        adapted for determining at least one respiratory parameter        (Rdiff, shunt,        , H-shift, V-shift) being descriptive of the condition of the        individual, the determination being based on the at least two        measurements.

Hence, in its broadest aspect, the invention relates to a device fordetermining one or more respiratory parameters-relating to anindividual. By the term “individual” is herein understood an individualselected from the group comprising humans as well as farm animals,domestic animals, pet animals and animals used for experiments such asmonkeys, rats, rabbits, etc.

By the term “respiratory parameters” is herein understood parametersrelating to oxygen transport from the lungs to the blood, such asparameters related to abnormal ventilation, resistance to oxygen uptakefrom the lungs to the lung capillary blood, and parameters related toshunting of venous blood to the arterial blood stream. These respiratoryparameters may be given as absolute values or relative values ascompared to a set of standard values and the parameters may further benormalised or generalised to obtain parameters that are comparable tosimilar parameters measured for other individuals, at least forindividuals of the same species.

Thus, the computer may further be adapted for determining at least tworespiratory parameters (Rdiff, shunt,

, H-shift, V-shift) being descriptive of the condition of theindividual, and said parameter(s) (Rdiff, shunt,

, H-shift, V-shift) may alternatively or additionally be generalisedparameters being comparable to similar parameter(s) determined for otherindividuals.

In a preferred embodiment, the computer of the device is further adaptedfor performing a procedure at least once, the procedure comprising

-   -   determining, based on at least two measurements, whether        additional measurements are required,    -   asserting a possible desired target defining a desired output of        the first detection means,    -   producing a possible control data item based on the target, and    -   retrieving and storing, in the data structure, additional        measurement results being the concurrent output produced by the        first detection means and the second detection means. The        control data item produced thereby may be outputted to a human        operator by means of an output device so that the operator can        adjust the level of oxygen in the inspired gas flow.        Alternatively, the control data item may be used by another part        of or a computer program within the computer or by an external        control device for automatically control of the means for        controlling the flow to the gas-mixing unit of at least one gas.

According to a preferred embodiment of the present invention, the seconddetection means are arranged for detecting the level (FIO₂, PIO₂) ofoxygen in the gas flow passing into the respiratory system, and thedevice further comprises

-   -   third detection means for detecting the level (FE′O₂, FĒO₂,        PE′O₂, PĒO₂) of oxygen in the gas flow passing out of the        respiratory system and producing an output to the computer        accordingly, and fourth detection means for detecting variables        (Vt, f,        ) of the gas flow passing the respiratory system and producing        an output to the computer accordingly, said output being        sufficient for the computer to establish the volume flow of gas        passing the respiratory system, the computer being adapted for        retrieving and storing output from the third detection means and        the fourth detection means within the data structure relating        these stored output mutually as well as with the output from the        first detection means and the second detection means retrieved        simultaneously. This/these measurement(s) enable(s) the computer        to estimate or establish the oxygen consumption of the        individual, either implicitly as part of the estimation of        respiratory parameters, or the computer may further be adapted        for explicitly establishing, based on said measurement(s), the        oxygen consumption (VO₂) of the individual.

It is advantageous for the device according to the present inventionthat the computer is adapted to determine a parameter relating to anequilibrium state of the overall oxygen uptake or consumption of theindividual based on the output of at least one of the detection means,to compare said parameter with a predefined threshold value and toproduce a control data item accordingly if said parameter exceeds saidthreshold value. By determining whether an equilibrium state of theindividual is obtained the timing of the steps of the procedure can becontrolled efficiently and the overall time for performing the proceduremay be further reduced.

It is also advantageous if the computer is adapted to asses theappropriate change in oxygen level in the inspired gas (FIO₂) from thecurrent oxygen level (FIO₂) so as to achieve a given desired targetoxygen level in the blood (SaO₂, SpO₂, PaO₂, PpO₂) and produce a controldata item accordingly so that the oxygen level can be adjusted accordingto the data item. The actual adjustment may be performed by an operatorof the device, in which case the data item is outputted to an outputdevice. Alternatively and preferably the computer is adapted to operatethe control means for controlling the flow to the gas mixing unit of atleast one gas, in response to said control data item relating to theassessed change in oxygen level from the computer so as to change theoxygen level (FIO₂) in the inspired gas flow accordingly. The data itemmay instead be outputted to an external device, which is suitable forperforming an automated control of the control means so as to adjust theoxygen level accordingly.

The assessment of change in oxygen level in the inspired gas may in anembodiment of the invention be based on a predefined set of datarepresenting statistical distributions of variables stored within datastorage means associated with the computer and on said measurements.Details of how this may be performed are disclosed in the detaileddescription of the invention. Alternatively, the assessment of change inoxygen level in the inspired gas may be based on the rate of change ofthe output of at least one of the detection means in response to achange in oxygen level (FIO₂) in the inspired gas flow. Typically, theoxygen level is changed stepwise or following a ramp function and thechange over time of the oxygen level in the blood circulation or thelevel of oxygen in the expired gas is monitored. However, monitoring ofanother gas, such as CO₂, or another variable of the patient mayadditionally or alternatively be employed.

It is preferred that one gas is atmospheric air and that another of thegasses is more or less pure oxygen, i.e. has an oxygen fraction higherthan that of atmospheric air, preferably in the range 0.85 to 1.00.Alternatively or additionally, another gas may be supplied which has anoxygen fraction below that of atmospheric air, i.e. in the range of 0.00to 0.21, preferably of 0.00 to 0.05. Thereby the oxygen level of theinspired gas may be varied not only to level above that of atmosphericair but also below that level, thus providing a wide range of possiblelevels for performing measurements of the individual. The gas having alow oxygen fraction may be supplied from a source of more or less purenitrogen N₂ or another suitable physiologically neutral gas, such ashelium H₂, or it may be re-circulated expired gas from the individual,preferably after reduction of the level of CO₂ in the expired gas.

The device should ensure by means of a security arrangement that theoxygen saturation in the blood circulation of the individual is in therange of 65 to 100%, preferably for human beings in the range of 85 to100% to avoid the risk of damage to organs. This condition varies fordifferent species of animals.

The first detection means is preferably arranged for detecting avariable relating to the saturation level of oxygen in the arterialblood stream by means of an invasive or a non-invasive technique, whichlatter is preferred. Thus, the first detection means is in anadvantageous embodiment a pulse oximeter. Alternatively, the level ofoxygen in the venous blood stream may be measured by means of aninvasive or a non-invasive technique, the latter again being thepreferred one.

According to a second aspect, the present invention relates to a devicefor determining one or more respiratory parameters relating to anindividual, comprising

-   -   a gas flow device having means for conducting a flow of        inspiratory gas from an inlet opening to the respiratory system        of the individual and a flow of expiratory gas from the        respiratory system of the individual to an outlet opening,    -   a gas-mixing unit for supplying a substantially homogeneous gas        to the inlet opening of the gas flow device,    -   first supply means for supplying a first gas to an inlet of the        gas mixing unit and having first control means for controlling        the flow of the first gas,    -   second supply means for supplying a second gas having an oxygen        fraction different to the gas supplied from the first supply        means to an inlet of the gas mixing unit and having second        control means for controlling the flow of the second gas,    -   a computer for determining said one or more respiratory        parameters,    -   first detection means for detecting the level of oxygen (SaO₂,        Spo₂, PaO₂, PpO₂) in the blood circulation of the individual and        producing an output to the computer accordingly, and    -   second detection means for detecting the level of oxygen (FIO₂,        FE′O₂, FĒO₂, PIO₂, PE′O₂, PĒO₂) in the gas flow passing into or        out of the respiratory system of the individual and producing an        output to the computer accordingly,    -   the computer being adapted for retrieving and storing a first        measurement being the concurrent output produced by the first        detection means and the second detection means within a data        structure, in which the two stored outputs are mutually related,        in data storage means associated with the computer, the computer        being further adapted for performing a procedure at least once,        the procedure comprising    -   determining, based on data stored within the data structure,        whether additional measurements are required,    -   asserting a possible desired target defining a desired output of        the first detection means,    -   producing a possible control data item based on the target, and    -   retrieving and storing, in the data structure, additional        measurement results being the concurrent output produced by the        first detection means and the second detection means.

According to a third aspect, the present invention relates to a devicefor determining one or more respiratory parameters relating to anindividual, comprising

-   -   a gas flow device having means for conducting a flow of        inspiratory gas from an inlet opening to the respiratory system        of the individual and a flow of expiratory gas from the        respiratory system of the individual to an outlet opening,    -   a gas-mixing unit for supplying a substantially homogeneous gas        to the inlet opening of the gas flow device,    -   first supply means for supplying a first gas to an inlet of the        gas mixing unit and having first control means for controlling        the flow of the first gas,    -   second supply means for supplying a second gas having an oxygen        fraction different to the gas supplied from the first supply        means to an inlet of the gas mixing unit and having second        control means for controlling the flow of the second gas,    -   a computer for determining said one or more respiratory        parameters,    -   first detection means for detecting the level of oxygen (SaO₂,        SpO₂, PaO₂, PpO₂) in the blood circulation of the individual and        producing an output to the computer accordingly, and    -   second detection means for detecting the level of oxygen (FIO₂,        FE′O₂, FĒO₂, PIO₂, PE′O₂, FĒO₂) in the gas flow passing into or        out of the respiratory system of the individual and producing an        output to the computer accordingly,    -   the computer being adapted for retrieving and storing at least a        first measurement being the concurrent output produced by the        first detection means and the second detection means within a        data structure, in which the two stored outputs are mutually        related, in data storage means associated with the computer, the        computer further being adapted to asses the appropriate change        in oxygen level in the inspired gas (FIO₂) from the current        oxygen level (FIO₂) so as to achieve a given desired target        oxygen level in the blood (SaO₂, SpO₂, PaO₂, PpO₂) and produce a        control data item accordingly.

The second aspect as well as the third aspect of the invention isdisclosed above in the most fundamental embodiment which according tothe present invention may be combined with the additional featuresdisclosed above with relation to the first aspect of the invention.

The device may be used to obtain and/or compare one or more respiratoryparameters relating to one or more individual(s). The individual may bea healthy individual, at risk of suffering from hypoxemia, or sufferingfrom hypoxemia.

By the term “the individual is at risk of suffering from hypoxemia” isherein understood that the individual has a higher/increased risk ofsuffering from hypoxemia compared to a healthy individual. The increasedrisk of suffering from hypoxemia may e.g. be due to a hereditarypredisposition, a post-operative condition and/or various diseases.

By the term “hypoxemia” is herein meant that the oxygen saturation inthe blood from the individual is below 92%. Examples of diseases thatcan cause hypoxemia are left sided heart failure, adult respiratorydistress syndrome, pneumonia, postoperative hypoxemia, pulmonaryfibrosis, toxic pulmonary lymphoedema, pulmonary embolisms, chronicobstructive pulmonary disease and cardiac shunting.

The present invention also relates to a computer system comprising atleast one general purpose computer having one or more computer programsstored within data storage means associated therewith, the computersystem being arranged for as well as being adapted for determining oneor more respiratory parameters according to the devices and/or methodsdisclosed above.

Furthermore, the present invention relates to a computer program productbeing adapted to enable a computer system comprising at least onegeneral purpose computer having data storage means associated therewithand being arranged suitably to determine one or more respiratoryparameters according to the devices and/or methods disclosed above.

GLOSSARY FIO2 Fraction of oxygen in inspired gas. PIO2 Pressure ofoxygen in inspired gas. SaO2 Oxygen saturation of arterial blood,measured from a blood sample. PaO2 Pressure of oxygen in arterial blood,measured from a blood sample. SpO2 Oxygen saturation of arterial blood,measured transcutaneously. PpO2 Pressure of oxygen in arterial blood,measured transcutaneously. FĒCO2 Fraction of carbon dioxide in the mixedexpired gas. FE'O2 Fraction of oxygen in expired gas at the end ofexpiration. FĒO2 Fraction of oxygen in the mixed expired gas. PĒCO2Pressure of oxygen in the mixed expired gas. PE'O2 Pressure of oxygen inexpired gas at the end of expiration. Vt Tidal volume, i.e. volume ofgas breathed per breath. f Respiratory frequency, i.e. number of breathsper minute. VO2 Oxygen consumption, i.e. the amount of oxygen consumedby the tissues per minute. Vd Dead space i.e. the volume of the lung notinvolved in exchanging gases with the blood. shunt Respiratory parameterrepresenting the faction of blood not involved in gas exchange. RdiffRespiratory parameter representing a resistance to oxygen diffusionacross the alveolar lung capillary membrane. {dot over (V)} Ventilation.{dot over (V)}/{dot over (Q)} Respiratory parameter representing thebalance between ventilation and perfusion in a region of the lung.V-shift Respiratory parameter representing a vertical shift in plots ofFIO2 against SaO2, FIO2 against SpO2, FE'O2 against SaO2, or FE'O2against SpO2. H-shift Respiratory parameter representing a horizontalshift in plots of FIO2 against SaO2, FIO2 against SpO2, FE'O2 againstSaO2, or FE'O2 against SpO2.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Plot of the inspired oxygen fraction (FIO₂, x-axis) against thearterial oxygen saturation (SaO₂, SpO₂, y-axis) for 1 patient. For eachdata point (A–D) the “effective shunt” has been estimated from a singleparameter shunt model (Siggaard-Andersen and Siggaard-Andersen 1985),giving values of point A=15%, point B=15%, point C=20%, point D=25%.

FIG. 2. Plots of the inspired oxygen fraction (FIO₂, x-axis) againstmodel predicted arterial oxygen saturation (SaO₂, SpO₂, y-axis) for 1) anormal subject with shunt=5% and Rdiff=0 kPa/I/min) (solid line), 2) ahypothetical patient with a Rdiff or ventilation/perfusion disorder(dotted line), and 3) a hypothetical patient with a shunt disorder(dashed line).

Line A illustrates the vertical displacement of the curve (V-shift) dueto a shunt disorder, whilst line B illustrates the horizontaldisplacement of the curve (H-shift) due to a ventilation perfusion ofoxygen diffusion abnormality.

FIG. 3. Plots of the inspired oxygen fraction (FIO₂, x-axis) againstarterial oxygen saturation (SaO₂, SpO₂, y-axis). Each of the vignettesillustrates data (crosses) and model predicted curves fitted, to thisdata from: A—a normal subject (shunt=5%, Rdiff=−1.5 kPa/(l/min)), B—apost-operative cardiac patient (shunt=9.5%, Rdiff=81.0 kPa/(l/min)), C—apost-operative hysterectomy patient (shunt=7%, Rdiff=15.2 kPa/(l/min)),D—a poorly compensated cardiac patient (shunt=15%, Rdiff=22.9kPa/(l/min)), and E—a patient residing in the intensive care unit(shunt=7%, Rdiff=31.0 kPa/(l/min)).

FIG. 4. Experimental set-up working with nitrogen for subathmosphericoxygen levels. The system includes: 1) A Gas Delivery Unit including gasinlets (1 a, 1 b), a gas mixer (1 c), a flow or pressure gradient (1 d),and equipment for the measurement and/or setting of inspired oxygenfraction (FIO₂), tidal volume and respiratory frequency (1 e); ₂)Equipment for measurement of expired gases including an oxygen monitorplaced so as to measure end tidal oxygen fraction (2 a), and/or anexpiratory reservoir, used with an oxygen monitor and/or a carbondioxide monitor to measure the fraction of gas in or leaving theexpiratory reservoir (FĒO₂, FĒCO₂) (2 b); 3) Measurement of arterialoxygen saturation (SaO₂) via e.g. a pulse oxymeter (SpO₂); 4)Measurements of arterial or venous blood gas samples (optional); 5)Measurement of cardiac output (optional); 6) A computer system includingsoftware for automatic collection of data (6 a), monitoring the steadystate of the patients/subjects oxygenation (6 b), a feedback controllerfor adjusting inspired oxygen fraction (6 c), and estimation of gasexchange parameters. Dashed arrowed lines illustrate the flow ofinformation to the computer. Dotted arrowed lines illustrated thecontrol of the gas delivery unit by the computer.

FIG. 5. Experimental set up using a rebreathing technique forsubatmospheric oxygen levels. FIG. 5 illustrates a modification to theset-up of FIG. 4. It includes all other components illustrated in FIG.4, plus a carbon dioxide removal device to eliminate carbon dioxide fromthe re-inspired gases (box 7). All other points 1–6 are the same as FIG.4.

FIG. 6. Flow chart for a measurement of variables for determination oflung parameters.

-   A: Begin parameter estimation if FIO₂>1.00 and SpO₂>0.85-   B: Continuous data recording from gas delivery unit, pulse oxymeter    and expiratory gas measurement devices.-   C: Set oxygen level (FIO₂).-   D: Monitor O₂ equilibrium.-   E: Equilibrium level.-   F: Record measurement.-   G: Sufficient number of measurements?-   H: Estimate new FIO₂.-   I: Estimate Pulmonary Parameters.

FIG. 7. (algorithm 1) Assessing whether another measurement is necessaryand determining the target SpO₂ for that measurement. If currentFIO₂=1.00 and SpO₂<0.85% do not perform measurement.

-   A: Is there 1 measurement of (SpO₂) 1 where 0.85≦(SpO₂) 1<0.92?-   B: Target SpO₂: 0.85≦(SpO₂) 1<0.92-   C: Was FIO₂=1.00 at this measurement?-   D: Patient too sick for measurement.-   E: Is there 1 measurement of (SpO₂) 2 where 0.92≦(SpO₂) 2<0.95?-   F: Target SpO₂: 0.92≦(SpO₂) 2 <0.95-   G: FIO₂=1.00 at this measurement?-   H: Target SpO₂: (SpO₂) 1≦SpO₂<(SpO₂) 2-   I: Is there 1 measurement of (SpO₂) 3 where 0.95≦(SpO₂) 3<0.98?-   J: Target SpO₂: 0.95≦(SpO₂) 3<0.98-   K: Was FIO₂=1.00 at this measurement?-   L: Target SpO₂: (SpO₂) 2≦SpO₂<(SpO₂) 3-   M: Set FIO₂=1.00.

FIG. 8 (algorithm 2) This controller uses a mathematical model of oxygentransport with two parameters, shunt and either diffusion resistance or

mismatch. Parameters are implemented as stochastic variables and as suchhave a probabilistic distribution.

A: Select Appropriate a Priori Estimates for Parameters

The patients lung parameters are represented as stochastic variableswith probability distributions. These parameters need to be initialisedwith a priori distributions. If the patients lung parameters have beeninvestigated previously, or if the patient belongs to a well-definedpopulation there may be well-defined a priori distributions for thepatient's lung parameters.

B: Target SpO₂=First Target Level

C: Update Parameter Estimates with Measurement Data.

This is a Bayesian update of the parameter estimates for the measuredvalues. The output of this process being revised probabilitydistributions for the patients' lung parameters.

D: Is the Parameter Probability Mass Distributed within Range.

If the probability distributions for the patients' lung parameters havea very narrow distribution, then they are estimated with good precision,and no further FIO₂ settings or measurements are required.

E: Predict SpO₂ (distribution) when FIO₂ lowered/raised by apredetermined percentage, using parameter estimates. The predeterminedpercentage is dependent on the conditions and the patient. Themathematical models can be used to predict the effects of varying FIO₂giving the current estimate of the probability distributions for thepatients' lung parameters. Predictions can be obtained in terms of theprobability of a certain oxygen saturation of the blood.F: Is 10% of Probability Mass <Target SpO₂.

If the predicted probability distribution for SpO₂ is distributed evenlyabout the target SpO₂ then the FIO₂ is selected for the nextmeasurement.

G: Set the Selected FIO₂ Level.

H: Continue the Algorithm only if there are more Target SpO₂ Levels?

I: Set the next Target SpO₂ Level.

FIG. 9 illustrates a graph of a patients parameter (A, x-axis) plottedagainst the probability that this parameter takes a certain value (P(A),y-axis). One of these graphs is used for each patient parameter (i.e.shunt, Rdiff and or

). Before a measurement procedure begins an a priori distribution isobtained for each of the patient parameters from computer storage.Subsequently, these a priori estimates are updated as measured datapresents. Typical distributions of the shunt parameter are illustratedfor a normal healthy subject both a priori (solid line, mean shunt=5%),and following update of the distribution with measured data (dashedline).

FIG. 10 illustrates model predicted arterial oxygen saturation (SaO₂,SpO₂, y-axis) when varying inspired oxygen fraction (FIO₂, x-axis).Points A and B are measured FIO₂/SpO₂ values which are used to updateparameter values (i.e. P(parameters|measurements)). The updatedparameter values are then used to predict the change in SpO₂ on varyingFIO₂ (i.e. P(SpO₂|FIO₂)). These predictions are illustrated for twodifferent FIO₂ levels (C and D) and are plotted as probabilitydistributions. The appropriate FIO₂ level is then selected so that ≦x%(in this case 10%) of the probability distribution is below the targetSpO₂ level (E).

DETAILED DESCRIPTION OF THE INVENTION

The following description of preferred embodiments of the invention willfocus on a device for automating the estimation of lung parameters. Thisdevice (Automatic Lung Parameter Estimator=ALPE) enables reduction inthe time taken to obtain estimates of oxygenation parameters, with thetotal time including on-line estimation of parameters taking 10–15minutes. By reducing the procedural time these techniques have potentialfor routine clinical use. This is only possible because of thesubstantial novelty in the ALPE which may include functionality for:

-   1) On-line continuous data collection-   2) Automatic assessment of the timing of measurements-   3) Automatic assessment of the next target SpO₂-   4) Automatic assessment of the appropriate FIO₂ settings to achieve    the target SpO₂-   5) Automatic control of the FIO₂-   6) On-line parameter estimation-   7) Automatic assessment of the number of measurements required

This functionality is achieved through a novel apparatus includingventilatory equipment, blood gas analysis equipment and computerhardware and software as described below.

Description of the Automatic Lung Parameter Estimator (ALPE):

The Automatic Lung Parameter Estimator (ALPE) illustrated in FIG. 4 maybe used to assess oxygenation parameters in any patient, with theseparameters being useful for diagnostic or monitoring purposes.Monitoring of patients' lung parameters is of particular value for thosepatients with ongoing treatment for example those patients artificiallyventilated or those receiving therapies for left-sided heart failure.

The ALPE can automatically determine the parameters of models of oxygentransport. These parameters are obtained from numerous measurementsincluding the FIO₂/SpO₂ curve, with this curve being constructedautomatically by the apparatus for SpO₂ varying between 0.85 to 1.00.

ALPE illustrated in FIG. 4 includes the following (numbers beforeparagraphs refer to the numbers in FIG. 4):

-   1) A Gas Delivery Unit—This equipment includes: Two or more gas    inlets, shown here delivering a) oxygen or nitrogen, and b) air; c)    A gas mixer capable of mixing two input gases to the required    fraction or concentration; d) A means of delivering the gases to the    patient/subject i.e. a flow or pressure gradient; e) Equipment for    the measurement and/or setting of inspired oxygen fraction (FIO₂),    tidal volume and respiratory frequency (or minute volume). The gas    delivery unit included in the system can either be a stand-alone    device offering only this functionality, or any other device, which    includes this functionality such as patient ventilation devices    (respirators) commonly used for intensive care patients. Ventilatory    gases are delivered to and removed from the patient/subject through    a face mask, mouth piece combined with a nose clip, laryngeal    endotracheal tube etc.-   2) Measurement of expired gases—Expired gases are measured using    either: a) An oxygen monitor, placed so as to measure expiratory    gases and sensitive enough to give measurement of the end tidal    oxygen fraction (FE′O₂), i.e. the fraction of oxygen in the expired    gases at the end of an expiration. b) An expiratory reservoir,    placed so as to capture expiratory gases during the course of the    expiration, used in combination with an oxygen monitor and/or a    carbon dioxide monitor sensitive enough to measure the fraction of    gas in or leaving the expiratory reservoir (FĒO₂, FĒCO₂).-   3) Measurement of arterial oxygen saturation (SaO₂) via e.g. a pulse    oxymeter (SpO₂).-   4) Measurements of arterial or venous blood gas samples may be taken    or may be monitored continuously by invasive means and put manually    into the system. These measurements are optional.-   5) Measurement of cardiac output may be put manually into the    system. This measurement is optional.-   6) A computer system including software for    -   a) Automatic collection of data from the gas delivery unit        (FIO₂, Vt, f), the expired gas measurement devices (FE′O₂, FĒO₂,        FĒCO₂ (optional)), and the pulse oxymeter (or any other measure        of SpO₂ or SaO₂).    -   b) Monitoring the steady state of the patients/subjects        oxygenation.    -   c) A feedback controller, which determines whether a further        measurement is required and automatically adjusts the inspired        oxygen fraction to the most appropriate level.    -   d) Estimation of gas exchange parameters from the data        collected.

Dashed arrowed lines on FIG. 4 illustrate the flow of information to thecomputer. Dotted arrowed lines illustrated the control of the gasdelivery unit by the computer.

A modification to the system is also included as part of this patent(FIG. 5). For environments where nitrogen (N₂) or anotherphysiologically neutral gas is not available the oxygen content ofinspired gases can be reduced lower than air (FIO_(2air)=21%) byre-breathing expired gases. In this situation, in addition to all othercomponents illustrated in FIG. 4 a carbon dioxide removal device isincluded in the system to eliminate carbon dioxide from the re-inspiredgases (box 7 FIG. 5). All other points 1–6 described above are the sameas FIG. 4.

DETAILED DESCRIPTION OF THE FLOWCHARTS

The flowcharts are provided solely to illustrate the invention byreference to specific embodiments. These flowcharts and the algorithmsincluded herein, while illustrating certain aspects of the invention, donot portray the limitations or circumscribe the scope of the disclosedinvention.

FIG. 6 is a flowchart illustrating the processes involved duringoperation of the ALPE.

Box A: After set-up of the equipment as illustrated in FIGS. 4 and 5 theparameter estimation procedure begins.

Box B: As part of this process the computer continuously collects datafrom the other equipment, including FIO₂ and SpO₂ (and/or FE′O₂, Vt, f,FĒO₂, FĒCO₂).

Box C: An initial inspired oxygen fraction is selected (FIO₂) anddelivered to the patient. This is done automatically via the computer ormanually by the doctor. Initially FIO₂ is usually that of air (21%) butany other value of FIO₂ can be used as the starting point for theexperiment. At all times the patient/subject is required to have anarterial oxygen saturation (SpO₂) greater than or equal to 0.85. Theinitial FIO₂ may therefore be set to a high level so as to achieveSpO₂≧0.85.

After setting the inspired oxygen level the patients' oxygen system willtake time to equilibrate. This usually occurs within 2–5 minutes afterthe perturbation. The equilibrium of the patients oxygen system ismonitored automatically by the “steady state monitor” software in thecomputer. This functionality substantially reduces the time taken toperform a parameter estimation and is only possible because of theapparatus.

Box D: The assessment of equilibrium can be performed using a number ofalgorithms, e.g. as follows:

-   1) The arterial oxygen saturation (SpO₂) remains constant within a    predefined range over a predefined time period.-   2) The difference between the fraction of oxygen in the inspired and    expired gas remains constant within a predefined interval over a    predefined time period.-   3) The calculated oxygen consumption (VO₂) remains constant within a    predefined interval for a predefined time period.

The oxygen consumption (VO₂) is calculated automatically by the computerfrom the continuously monitored variables using the equationVO₂=f(Vt−Vd) (FIO₂−FE′O₂) assuming or calculating a value of Vd, orusing VO₂=fVt(FIO₂−FĒO₂), or any variation in this equation where acombination of measurements of end tidal or mixed expired gases are usedto estimate the oxygen consumption.

Box E: When equilibrium is achieved a measurement is recorded (Box F).

Box F: This measurement includes the current values of all continuouslymonitored variables as described previously. It can also includemeasurements of blood gases in from and arterial or venous blood and acardiac output measure obtained from equipment e.g. a pulmonarycatheter. The last measurements are optional.

Box G: Following a measurement it is decided either automatically by theapparatus or manually by the clinician whether a sufficient number ofmeasurements have been performed, or whether to change the inspiredoxygen fraction to a new level and take a further measurement whenequilibrium is achieved.

Box H: It is also decided either automatically by the apparatus ormanually by the clinician what level of FIO₂ should be selected for anew measurement (if necessary). An experiment consists of not less than2 measurements at varying FIO₂ levels, with SpO₂ in the range 0.85–1.00.It is important that the setting of FIO₂ levels achieve data points withSpO₂ well distributed between 0.85–1.00.

Examples of algorithms, which can be used to implement Box G and Box Hare included in the next section.

Box I: After an adequate set of measurements has been taken parametersare estimated which describe the patients lung function. Parameterestimation is performed automatically using one or more of the followingalgorithms:

-   1) Graphical estimation of displacement(s) of the FIO₂/SpO₂ curve or    the FĒO₂/SpO₂ curve.

Values of inspired or expired oxygen fraction can be plotted against thearterial oxygen saturation (SpO₂) and graphical methods used to measurethe horizontal (H-shift) and vertical displacement (V-shift) of the data(or interpolated data) from a normal reference range as illustrated inFIG. 2.

-   2) Estimation of the parameters of models of oxygen transport.    -   All data collected for each of the measurements can be used with        mathematical models of oxygen transport to estimate parameters        describing oxygenation. Parameters can e.g. be estimated        describing the shunting of pulmonary blood (shunt) and either a        resistance to oxygen diffusion or a mismatch between the        ventilation and perfusion of the lung.

Algorithms for Automating boxes G and H in FIG. 6:

Numerous algorithms can be devised which enable assessment of:

-   -   a) Whether a new measurement is required.    -   b) What is the target SpO₂ for this measurement.    -   c) What inspired oxygen fraction (FIO₂) setting should be used        to obtain the target SpO₂

These algorithms include those with complete computer automation ofpoints a–c, and where points a–c are assessed using clinical judgement.

Two examples of these algorithms are presented here. The first includespoints a and b. The second includes points a and c, using mathematicalmodels of oxygen transport to asses the appropriate FIO₂ setting.

It should be noted that these algorithms are only illustrations of thecontrol system of ALPE and that any other algorithms which can be usedto assess points a, b and c are included in the patent application.

Algorithm 1: This algorithm covers points a and b above, and isillustrated in a flowchart (FIG. 7). It should be noted that if thecurrent FIO₂=1.0 and the current SpO₂ is <0.85, then the patient is tooill to perform a lung assessment.

Algorithm 2: This algorithm covers points a and c i.e. it assesseswhether a measurement is required and estimates the appropriate FIO₂setting for the next measurement given a target SpO₂. The algorithm isillustrated in the flowchart FIG. 8. This algorithm uses a mathematicalmodel of oxygen transport with two parameters. Parameters areimplemented as stochastic variables and as such have probabilitydistributions as illustrated in FIG. 9.

In box A (FIG. 9) the appropriate a priori estimates are obtained forthe parameter distributions. If the patients lung parameters have beeninvestigated previously, or if the patient belongs to a well-definedpopulation there may be well defined a priori distributions for thepatient's lung parameters. Alternatively, default parameter settings canbe used. An example illustrating probability distributions on aparameter e.g. “shunt” or diffusion resistance “Rdiff” is illustrated inFIG. 9.

In box B the predefined target SpO₂ level is retrieved from computerstorage.

In box C the parameters' probability distributions are updated with themeasured data.

This is a Bayesian update of the parameter estimates for the measuredvalues, such that the probability of the parameter values given themeasurements (P(parameters|measurements)) can be calculated from Bayestheorem i.e.${P\left( {parameters} \middle| {measurements} \right)} = \frac{{P\left( {measurements} \middle| {parameters} \right)}\mspace{11mu}{P({parameters})}}{P({measurements})}$

The output of this process being revised probability distributions forthe patients' lung parameters updated to reflect the new informationobtained from the measurements. These probability distributions areusually somewhat narrower than the a priori estimates as illustrated inFIG. 9.

Box D decides whether a further measurement is required. If the updatedprobability distributions for the patients' lung parameters have a verynarrow distribution, then they are estimated with good precision, and nofurther FIO₂ settings or measurements are required. If a furthermeasurement is required then it is necessary to find the appropriateFIO₂ setting so as to reach the next target SpO₂. This is done inseveral steps: first the mathematical models are used to predict SpO₂when the FIO₂ level is lowered or raised by a predetermined percentage.The predetermined percentage is dependent on the conditions and thepatient. SpO₂ is then predicted using the updated parameter estimatesand the equation:${P\left( {SpO2} \middle| ({FlO2}) \right)} = {\sum\limits_{param}{{P\left( {\left. {SpO2} \middle| {FlO2} \right.,{parameters}} \right)}\mspace{11mu}{P({parameters})}}}$where P(parameters) is the current joint probability of all theparameter estimates. The output from this procedure is a set ofprobability distributions about SpO₂ on varying FIO₂ values, asillustrated in FIG. 10. Next (box F), an FIO₂ level is selected. TheFIO₂ level is chosen such that a small fraction (e.g. 10%) of thepredicted probability mass is below the target SpO₂ (see FIG. 10).Selecting an FIO₂ where only a small fraction of the predicted SpO₂probability mass is below the target is a safety feature of thisalgorithm. Effectively, it means that it is unlikely that the patientsSpO₂ will fall below the target value on modification of FIO₂. Aftersetting the new FIO₂ level the SpO₂ target is modified and the aboveprocedure repeated.

REFERENCES

-   Andreassen, S., Egeberg, J., Schröter, M. P., Andersen, P.    T., (1996) Estimation of pulmonary diffusion resistance and shunt in    an oxygen status model. Comput Methods Programs Biomed, vol 51, pp    95–105.-   Andreassen, S., Rees, S. E., Kjaergaard, S., Thorgaard, P.,    Winter, S. M., Morgan, C. J., Alstrup, P., and Toft, E. (1999).    Hypoxemia after coronary bypass surgery modeled by resistance to    oxygen diffusion. Critical Care Medicine, vol 27, pp 2445–2453.-   de Gray, L., Rush, E. M., Jones, J. G., (1997). A non-invasive    method for evaluating the effect of thoracotomy on shunt and    ventilation perfusion inequality. Anaesthesia, vol. 52, pp 630–635.-   King, T. K. C, Weber, B., Okinaka, A., Friedman, S. A., Smith, J.    P., Briscoe, W. A. (1974). Oxygen transfer in catastrophic    respiratory failure. Chest, vol. 65, pp 40S–44S.-   Rees, S. E., Rutledge G. W., Andersen P. T., Andreassen, S. (1997).    Are alveolar block and ventilation-perfusion mismatch    distinguishable in routine clinical data. In: Proceedings of the    European society of computers in anaesthesia and intensive care    conference, Erlangen, Germany, Sep. 18–19, 1997.-   Riley, R. L., Counard A. (1951a) Analysis of factors affecting    partial pressure of oxygen and carbon dioxide in gas and blood of    the lungs: Theory. J Applied Physiol., vol 4, pp 77–101.-   Riley, R. L., Counard A., Donald, K. W. (1951b). Analysis of factors    affecting partial pressure of oxygen and carbon dioxide in gas and    blood of the lungs: Method. J. Applied Physiol., vol 4, pp 102–120.-   Roe P. G., Galdeirab, R., Sapsford., Jones, J. G. (1997).    Intra-operative gas exchange and post-operative hypoxaemia. European    Journal of Anaesthesiology, vol 14, pp 203–210.-   Sapsford, D. J., Jones J. G. (1995). The PiO2 vs. SpO₂ diagram: a    non-invasive measure of pulmonary oxygen exchange. European Journal    of Anaesthesiology, vol 12, pp 369–374.-   Siggaard-Andersen M, Siggaard-Andersen 0 (1995). Oxygen status    algorithm, version 3, with some applications, Acta Anaesthesiol    Scand. Vol. 39, Supp. 107, pp 13–20.-   Wagner, P. D., Saltzman, H. A., West, J. B. (1974). Measurement of    continuous distributions of ventilation-perfusion ratios: theory. J.    Appl. Physiol. Vol 36(5): 588–599.-   Wagner, P. D., Hedenstiema, G., Bylin, G. (1987).    Ventilation-perfusion inequality in chronic asthma. Am. Rev. Respir.    Dis., vol. 136, pp 605–612.

1. A device for determining one or more respiratory parameters relatingto an individual, comprising a gas flow device having means forconducting a flow of inspiratory gas from an inlet opening to therespiratory system of the individual and a flow of expiratory gas fromthe respiratory system of the individual to an outlet opening, agas-mixing unit for supplying a substantially homogeneous gas to theinlet opening of the gas flow device, first supply means for supplying afirst gas to an inlet of the gas mixing unit and having first controlmeans for controlling the flow of the first gas, second supply means forsupplying a second gas having an oxygen fraction different to the gassupplied from the first supply means to an inlet of the gas mixing unitand having second control means for controlling the flow of the secondgas, a computer for determining said one or more respiratory parameters,first detection means for detecting the level of oxygen (SaO₂, SpO₂,PaO₂, PpO₂) in the blood circulation of the individual and producing anoutput to the computer accordingly, and second detection means fordetecting the level of oxygen (FIO₂, FE′O₂, FĒO₂, PIO₂, PE′O₂, PĒO₂) inthe gas flow passing into or out of the respiratory system of theindividual and producing an output to the computer accordingly, thecomputer being adapted for retrieving and storing at least twomeasurements being the concurrent output produced by the first detectionmeans and the second detection means within a data structure, in whichthe two stored outputs are mutually related, in data storage associatedwith the computer, the at least two measurements being conducted atcorresponding levels of oxygen in the gas flow passing into therespiratory system, the computer further being adapted for determiningat least two respiratory parameter (Rdiff, shunt,

, H-shift, V-shift) being descriptive of the pulmonary gas exchange ofthe individual, the determination being based on the at least twomeasurements.
 2. A device according to claim 1, wherein saidparameter(s) (Rdiff, shunt,

, H-shift, V-shift) is/are generalised parameters being comparable tosimilar parameter(s) determined for other individuals.
 3. A deviceaccording to claim 1, wherein the computer further is adapted forperforming a procedure at least once, the procedure comprisingdetermining, based on at least two measurements, whether additionalmeasurements are required, asserting a possible desired target defininga desired output of the first detection means, producing a possiblecontrol data item based on the target, and retrieving and storing, inthe data structure, additional measurement results being the concurrentoutput produced by the first detection means and the second detectionmeans.
 4. A device according to claim 1, wherein the second detectionmeans are arranged for detecting the level (FIO2, PIO2) of oxygen in thegas flow passing into the respiratory system, and the device furthercomprises third detection means for detecting the level (FE′O2, FĒO2,PE′O2, PĒO2) of oxygen in the gas flow passing out of the respiratorysystem and producing an output to the computer accordingly, and fourthdetection means for detecting variables (Vt, f,

) of the gas flow passing the respiratory system and producing an outputto the computer accordingly, said output being sufficient for thecomputer to establish the volume flow of gas passing the respiratorysystem, the computer being adapted for retrieving and storing outputfrom the third detection means and the fourth detection means within thedata structure relating these stored output mutually as well as with theoutput from the first detection means and the second detection meansretrieved simultaneously.
 5. A device according to claim 4, wherein thecomputer further being adapted for establishing, based on saidmeasurement(s), the oxygen consumption (VO₂) of the individual.
 6. Adevice according to claim 1, wherein the computer is adapted todetermine a parameter relating to an equilibrium state of the overalloxygen uptake or consumption of the individual based on the output of atleast one of the detection means, to compare said parameter with apredefined threshold value and to produce a control data itemaccordingly if said parameter exceeds said threshold value.
 7. A deviceaccording to claim 1, wherein the computer is adapted to assess theappropriate change in oxygen level in the inspired gas (FIO2) from thecurrent oxygen level (FIO2) so as to achieve a given desired targetoxygen level in the blood (SaO2, SpO2, PaO2, PpO2) and produce a controldata item accordingly.
 8. A device according to claim 7, wherein theassessment of change in oxygen level in the inspired gas is based on apredefined set of data representing statistical distributions ofparameters stored within data storage associated with the computer andon said measurements.
 9. A device according to claim 7, wherein theassessment of change in oxygen level in the inspired gas is based on therate of change of the output of at least one of the detection means inresponse to a change in oxygen level (FIO₂) in the inspired gas flow.10. A device according to claim 7, wherein the computer is adapted tooperate the control means for controlling the flow to the gas mixingunit of at least one gas, in response to said control data item relatingto the assessed change in oxygen level from the computer so as to changethe oxygen level (FIO2) in the inspired gas flow accordingly.
 11. Adevice according to claim 1, wherein one gas is atmospheric air andanother gas has an oxygen fraction higher than that of atmospheric air.12. A device according to claim 11, wherein one gas is atmospheric airand another gas has an oxygen fraction higher than that of atmosphericair and in the range of 0.85 to 1.00.
 13. A device according to claim 1,wherein one gas is atmospheric air and another gas has an oxygenfraction in the range of 0.00 to 0.21.
 14. A device according to claim13, wherein one gas is atmospheric air and another gas has an oxygenfraction in the range 0.00 to 0.05.
 15. A device according to claim 1,wherein the oxygen saturation in the blood circulation of the individualis in the range of 65 to 100%.
 16. A device according to claim 15,wherein the oxygen saturation in the blood circulation of the individualis in the range of 85 to 100%.
 17. A device according to claim 1,wherein the first detection means is arranged for detecting a parameterrelating to the saturation level of oxygen in the arterial blood stream.18. A device for determining one or more respiratory parameters relatingto an individual, comprising a gas flow device having means forconducting a flow of inspiratory gas from an inlet opening to therespiratory system of the individual and a flow of expiratory gas fromthe respiratory system of the individual to an outlet opening, agas-mixing unit for supplying a substantially homogeneous gas to theinlet opening of the gas flow device, first supply means for supplying afirst gas to an inlet of the gas mixing unit and having first controlmeans for controlling the flow of the first gas, second supply means forsupplying a second gas having an oxygen fraction different to the gassupplied from the first supply means to an inlet of the gas mixing unitand having second control means for controlling the flow of the secondgas, a computer for determining said one or more respiratory parameters,first detection means for detecting the level of oxygen (SaO₂, SpO₂,PaO₂, PpO₂) in the blood circulation of the individual and producing anoutput to the computer accordingly, and second detection means fordetecting the level of oxygen (FIO₂, FE′O₂, FĒO₂, PIO₂, PE′O₂, PĒO₂) inthe gas flow passing into or out of the respiratory system of theindividual and producing an output to the computer accordingly, thecomputer being adapted for retrieving and storing a first measurementbeing the concurrent output produced by the first detection means andthe second detection means within a data structure, in which the twostored outputs are mutually related, in data storage associated with thecomputer, the computer being further adapted for performing a procedureat least once, the procedure comprising determining, based on datastored within the data structure, whether additional measurements arerequired, asserting a possible desired target defining a desired outputof the first detection means, producing a possible control data itembased on the target, and retrieving and storing, in the data structure,additional measurement results being the concurrent output produced bythe first detection means and the second detection means.
 19. A deviceaccording to claim 18, wherein the second detection means are arrangedfor detecting the level (FIO₂, PIO₂) of oxygen in the gas flow passinginto the respiratory system, and the device further comprises thirddetection means for detecting the level (FE′O₂, FĒO₂, PE′O₂, PĒO₂) ofoxygen in the gas flow passing out of the respiratory system andproducing an output to the computer accordingly, and fourth detectionmeans for detecting variables (Vt, f,

) of the gas flow passing the respiratory system and producing an outputto the computer accordingly, said output being sufficient for thecomputer to establish the volume flow of gas passing the respiratorysystem, the computer being adapted for retrieving and storing outputfrom the third detection means and the fourth detection means within thedata structure in data storage associated with the computer, in whichthe stored outputs are mutually related and related to the output fromthe first detection means and the second detection means, and the outputfrom the four detection means can be retrieved simultaneously.
 20. Adevice according to claim 19, wherein the computer further being adaptedfor establishing, based on said measurement(s), the oxygen consumption(VO₂) of the individual.
 21. A device according to claim 18, wherein thecomputer is adapted for determining at least one respiratory parameter(Rdiff, shunt,

, H-shift, V-shift) being descriptive of the condition of theindividual, the determination being based on at least two measurements.22. A device according to claim 21, wherein at least two respiratoryparameters (Rdiff, shunt,

, H-shift, V-shift) are determined.
 23. A device according to claim 21,wherein said parameter(s) (Rdiff, shunt,

, H-shift, V-shift) is/are generalised parameters being comparable tosimilar parameter(s) determined for other individuals.
 24. A deviceaccording to claim 18, wherein the computer is adapted to determine aparameter relating to an equilibrium state of the overall oxygen uptakeor consumption of the individual based on the output of at least one ofthe detection means, to compare said parameter with a predefinedthreshold value and to produce a control data item accordingly if saidparameter exceeds said threshold value.
 25. A device according to claim18, wherein the computer is adapted to assess the appropriate change inoxygen level in the inspired gas (FIO2) from the current oxygen level(FIO2) so as to achieve a given desired target oxygen level in the blood(SaO2, SpO2, PaO2, PpO2) and produce a control data item accordingly.26. A device according to claim 25, wherein the assessment of change inoxygen level in the inspired gas is based on a predefined set of datarepresenting statistical distributions of parameters stored within datastorage means associated with the computer and on said measurement(s).27. A device according to claim 25, wherein the assessment of change inoxygen level in the inspired gas is based on the rate of change of theoutput of at least one of the detection means in response to a change inoxygen level (FIO₂) in the inspired gas flow.
 28. A device according toclaim 25, wherein the computer is adapted to operate the control meansfor controlling the flow to the gas mixing unit of at least one gas, inresponse to said control data item relating to the assessed change inoxygen level from the computer so as to change the oxygen level (FIO2)in the inspired gas flow accordingly.
 29. A device according to claim18, wherein one gas is atmospheric air and another gas has an oxygenfraction higher than that of atmospheric air.
 30. A device according toclaim 29, wherein one gas is atmospheric air and another gas has anoxygen fraction higher than that of atmospheric air and in the range0.85 to 1.00.
 31. A device according to claim 18, wherein one gas isatmospheric air and another gas has an oxygen fraction in the range of0.00 to 0.21.
 32. A device according to claim 31, wherein one gas isatmospheric air and another gas has an oxygen fraction in the range of0.00 to 0.05.
 33. A device according to claim 18, wherein the oxygensaturation in the blood circulation of the individual is in the range of65 to 100%.
 34. A device according to claim 33, wherein the oxygensaturation in the blood circulation of the individual is in the range of85 to 100%.
 35. A device according to claim 18, wherein the firstdetection means is arranged for detecting a parameter relating to thesaturation level of oxygen in the arterial blood stream.
 36. A devicefor determining one or more respiratory parameters relating to anindividual, comprising a gas flow device having means for conducting aflow of inspiratory gas from an inlet opening to the respiratory systemof the individual and a flow of expiratory gas from the respiratorysystem of the individual to an outlet opening, a gas-mixing unit forsupplying a substantially homogeneous gas to the inlet opening of thegas flow device, first supply means for supplying a first gas to aninlet of the gas mixing unit and having first control means forcontrolling the flow of the first gas, second supply means for supplyinga second gas having an oxygen fraction different to the gas suppliedfrom the first supply means to an inlet of the gas mixing unit andhaving second control means for controlling the flow of the second gas,a computer for determining said one or more respiratory parameters,first detection means for detecting the level of oxygen (SaO₂, SpO₂,PaO₂, PpO₂) in the blood circulation of the individual and producing anoutput to the computer accordingly, and second detection means fordetecting the level of oxygen (FIO₂, FE′O₂, FĒO₂, PIO₂, PE′O₂, FĒO₂) inthe gas flow passing into or out of the respiratory system of theindividual and producing an output to the computer accordingly, thecomputer being adapted for retrieving and storing at least a firstmeasurement being the concurrent output produced by the first detectionmeans and the second detection means within a data structure, in whichthe two stored outputs are mutually related, in data storage associatedwith the computer, the computer further being adapted to assess theappropriate change in oxygen level in the inspired gas (FIO₂) from thecurrent oxygen level (FIO₂) so as to achieve a given desired targetoxygen level in the blood (SaO₂, SpO₂, PaO₂, PpO₂) and produce a controldata item accordingly, wherein the assessment of change in oxygen levelin the inspired gas is based on a predefined set of data representingstatistical distributions of parameters stored within data storage meansassociated with the computer and on said measurement(s).
 37. A deviceaccording to claim 36, wherein the assessment of change in oxygen levelin the inspired gas is based on the rate of change of the output of atleast one of the detection means in response to a change in oxygen level(FIO₂) in the inspired gas flow.
 38. A device according to claim 36,wherein the computer is adapted to operate the control means forcontrolling the flow to the gas mixing unit of at least one gas, inresponse to said control data item from the computer so as to change theoxygen level (FIO2) in the inspired gas flow accordingly.
 39. A deviceaccording to claim 36, wherein the computer further is adapted forperforming a procedure at least once, the procedure comprisingdetermining, based on at least one measurement, whether additionalmeasurements are required, asserting a possible desired target defininga desired output of the first detection means, producing a possiblecontrol data item based on the target, and retrieving and storing, inthe data structure, additional measurement results being the concurrentoutput produced by the first detection means and the second detectionmeans.
 40. A device according to claim 36, wherein the second detectionmeans are arranged for detecting the level (FIO2, PIO2) of oxygen in thegas flow passing into the respiratory system, and the device furthercomprises third detection means for detecting the level (FE′O2, FĒO₂,PE′O2, PĒO2) of oxygen in the gas flow passing out of the respiratorysystem and producing an output to the computer accordingly, and fourthdetection means for detecting variables (Vt, f,

) of the gas flow passing the respiratory system and producing an outputto the computer accordingly, said output being sufficient for thecomputer to establish the volume flow of gas passing the respiratorysystem, the computer being adapted for retrieving and storing outputfrom the third detection means and the fourth detection means within thedata structure relating these stored output mutually as well as with theoutput from the first detection means and the second detection meansretrieved simultaneously.
 41. A device according to claim 40, whereinthe computer further being adapted for establishing, based on saidmeasurement(s), the oxygen consumption (VO₂) of the individual.
 42. Adevice according to claim 36, wherein the computer is adapted fordetermining at least one respiratory parameter (Rdiff, shunt,

, H-shift, V-shift) being descriptive of the condition of theindividual, the determination being based on at least two measurements.43. A device according to claim 42, wherein at least two respiratoryparameters (Rdiff, shunt,

, H-shift, V-shift) are determined.
 44. A device according to claim 42,wherein said parameter(s) (Rdiff, shunt,

, H-shift, V-shift) is/are generalized parameters being comparable tosimilar parameter(s) determined for other individuals.
 45. A deviceaccording to claim 36, wherein the computer is adapted to determine aparameter relating to an equilibrium state of the overall oxygen uptakeor consumption of the individual based on the output of at least one ofthe detection means, to compare said parameter with a predefinedthreshold value and to produce a control data item accordingly if saidparameter exceeds said threshold value.
 46. A device according to claim36, wherein one gas is atmospheric air and another gas has an oxygenfraction higher than that of atmospheric air.
 47. A device according toclaim 36, wherein one gas is atmospheric air and another gas has anoxygen fraction in the range of 0.00 to 0.21.
 48. A device according toclaim 36, wherein the oxygen saturation in the blood circulation of theindividual is in the range of 65 to 100%.
 49. A device according toclaim 36, wherein the first detection means is arranged for detecting aparameter relating to the saturation level of oxygen in the arterialblood stream.
 50. Method for determining one or more respiratoryparameters using a device according to claim 36, wherein the individualis an apparently healthy individual.
 51. Method for determining one ormore respiratory parameters using a device according to claim 36,wherein the individual is considered to have a risk of suffering fromhypoxemia.
 52. Method for determining one or more respiratory parametersusing a device according to claim 36, wherein the individual issuffering from hypoxemia.
 53. Method according to claim 52, wherein theindividual is suffering from one or more disease(s) selected from thegroup(s) comprising left sided heart failure, adult respiratory distresssyndrome, pneumonia, postoperative hypoxemia, pulmonary fibrosis, toxicpulmonary lymphoedema, pulmonary embolisms, chronic obstructivepulmonary disease and cardiac shunting.
 54. A device according to claim36, wherein one gas is atmospheric air and another gas has an oxygenfraction higher than that of atmospheric air and in the range of 0.85 to1.00.
 55. A device according to claim 36, wherein one gas is atmosphericair and another gas has an oxygen fraction in the range of 0.00 to 0.05.56. A device according to claim 36, wherein the oxygen saturation in theblood circulation of the individual is in the range of 85 to 100%.
 57. Acomputer system comprising at least one general purpose computer havingone or more computer programs stored within data storage meansassociated therewith, the computer system being arranged for as well asbeing adapted for determining one or more respiratory parametersrelating to an individual, the computer system being intended for usewith an associated gas flow device having means for conducting a flow ofinspiratory gas from an inlet opening to the respiratory system of theindividual and a flow of expiratory gas from the respiratory system ofthe individual to an outlet opening, an associated gas-mixing unit forsupplying a substantially homogeneous gas to the inlet opening of thegas flow device, associated first supply means for supplying a first gasto an inlet of the gas mixing unit and having first control means forcontrolling the flow of the first gas, associated second supply meansfor supplying a second gas having an oxygen fraction different to thegas supplied from the first supply means to an inlet of the gas mixingunit and having second control means for controlling the flow of thesecond gas, associated first detection means for detecting the level ofoxygen (SaO₂, SpO₂, PaO₂, PpO₂) in the blood circulation of theindividual and producing an output to the computer system accordingly,and associated second detection means for detecting the level of oxygen(FIO₂, FE′O₂, FĒO₂, PIO₂, PE′O₂, PĒO₂) in the gas flow passing into orout of the respiratory system of the individual and producing an outputto the computer system accordingly, the computer system being adaptedfor retrieving and storing at least two measurements being theconcurrent output produced by the first detection means and the seconddetection means within a data structure, in which the two stored outputsare mutually related, in data storage associated with the computersystem, the at least two measurements being conducted at correspondinglevels of oxygen in the gas flow passing into the respiratory system,the computer system further being adapted for determining at least tworespiratory parameters (Rdiff, shunt,

, H-shift, V-shift) being descriptive of the pulmonary gas exchange ofthe individual, the determination being based on the at least twomeasurements.
 58. A computer program product embodied on a computerreadable medium being adapted to enable a computer system according toclaim 57 to determine one or more respiratory parameters of anindividual.